Publications by Maria Ceprian

Neuroglial CB1 receptors modulate hippocampal processes in a sex-dependent manner

• Authors: Jon Egaña-Huguet # 1 2, Lucía Sangroniz-Beltrán # 1 2, Andrés M Baraibar 1 2 3, Pablo Reyes-Velásquez 1 2, Nicolas F Landgraf 1 2, Paula Torres-Maldonado 1 2, Cathaysa Rodríguez-Cedrés 1 2, Francisca Julio-Kalajzic 4, Joaquín Piriz 2 5, Almudena Ramos 1 2, Pedro Grandes 1 2, Giovanni Marsicano 4, Susana Mato 1 2 3, María Ceprián 6 7, Edgar Soria-Gómez 8 9 10

• Publication date: 2026 Mar 19

• Background: Navigation and memory are hippocampal functions that are essential for survival. One of the key modulators of hippocampal activity is the endocannabinoid system through the cannabinoid receptor type 1 (CB1). CB1 is widely expressed in various types of hippocampal cells. While it is known that CB1 participates in memory processes, its specific roles in different cell types and differences between sexes remain unclear.

• Methods: This study investigates the cell- and sex-specific modulation of navigation and memory by CB1 receptors. To this end, we selectively deleted CB1 receptors from hippocampal neurons or astrocytes in adult male and female mice. We then assessed its effect on a comprehensive range of behaviors, including innate emotional responses, memory, navigation, and nesting.

• Results: Deletion of CB1 from hippocampal principal cells or astrocytes produced significant changes in innate emotional behavior and novel object recognition in both sexes. Conversely, CB1 receptor deletion from all neurons produced deficits in spatial navigation exclusively in males. Interestingly, synaptic plasticity was impaired in both male and female mice lacking CB1 receptors from GFAP-positive cells. Nest-building behavior was only affected in males carrying the CB1 deletion in CAMK-positive cells.

• Conclusion: In conclusion, our findings show that neuronal CB1 receptors are critical for spatial navigation in males, while astrocytic CB1 receptors play a key role in memory processes in both males and females.

• Keywords: Astrocytes; CB1 receptors; Hippocampus; Memory; Navigation; Neurons; Sex differences.

• Authors: Maria Ceprian 1, Raul Juntas-Morales 2 3, Graham Campbell 1, Ulrike Walther-Louvier 4, François Rivier 4, William Camu 2, Florence Esselin 2, Andoni Echaniz-Laguna 5, Tanya Stojkovic 6, Françoise Bouhour 7, Philippe Latour 8, Nicolas Tricaud 1 9

• Publication date: 2024 Apr 15

• Abstract: Demyelinating Charcot-Marie-Tooth 4G (CMT4G) results from a recessive mutation in the 5'UTR region of the Hexokinase 1 (HK1) gene. HK participates in mitochondrial calcium homeostasis by binding to the Voltage-Dependent Anion Channel (VDAC), through its N-terminal porin-binding domain. Our hypothesis is that CMT4G mutation results in a broken interaction between mutant HK1 and VDAC, disturbing mitochondrial calcium homeostasis. We studied a cohort of 25 CMT4G patients recruited in the French gypsy population. The disease was characterized by a childhood onset, an intermediate demyelinating pattern, and a significant phenotype leading to becoming wheelchair-bound by the fifth decade of life. Co-IP and PLA studies indicated a strong decreased interaction between VDAC and HK1 in the patients' PBMCs and sural nerve. We observed that either wild-type HK1 expression or a peptide comprising the 15 aa of the N-terminal wild-type HK1 administration decreased mitochondrial calcium release in HEK293 cells. However, mutated CMT4G HK1 or the 15 aa of the mutated HK1 was unable to block mitochondrial calcium release. Taken together, these data show that the CMT4G-induced modification of the HK1 N-terminus disrupts HK1-VDAC interaction. This alters mitochondrial calcium buffering that has been shown to be critical for myelin sheath maintenance.

• Authors: Andrés Vicente-Acosta 1 2, Maria Ceprian 3, Pilar Sobrino 4, Maria Ruth Pazos 5, Frida Loría 5

• Publication date: 2022 Jun 1

• Abstract: Stroke is the second leading cause of death worldwide following coronary heart disease. Despite significant efforts to find effective treatments to reduce neurological damage, many patients suffer from sequelae that impair their quality of life. For this reason, the search for new therapeutic options for the treatment of these patients is a priority. Glial cells, including microglia, astrocytes and oligodendrocytes, participate in crucial processes that allow the correct functioning of the neural tissue, being actively involved in the pathophysiological mechanisms of ischemic stroke. Although the exact mechanisms by which glial cells contribute in the pathophysiological context of stroke are not yet completely understood, they have emerged as potentially therapeutic targets to improve brain recovery. The endocannabinoid system has interesting immunomodulatory and protective effects in glial cells, and the pharmacological modulation of this signaling pathway has revealed potential neuroprotective effects in different neurological diseases. Therefore, here we recapitulate current findings on the potential promising contribution of the endocannabinoid system pharmacological manipulation in glial cells for the treatment of ischemic stroke.

• Authors: Benoit Gautier 1, Helene Hajjar 2 3, Sylvia Soares 4, Jade Berthelot 2, Marie Deck 2, Scarlette Abbou 2, Graham Campbell 2, Maria Ceprian 2 5, Sergio Gonzalez 2 5, Claire-Maëlle Fovet 6, Vlad Schütza 7, Antoine Jouvenel 2, Cyril Rivat 2, Michel Zerah 8, Virginie François 9, Caroline Le Guiner 9, Patrick Aubourg 10 11, Robert Fledrich 12, Nicolas Tricaud 13 14 15

• Publication date: 2021 Apr 21

• Abstract: Charcot-Marie-Tooth disease 1 A (CMT1A) results from a duplication of the PMP22 gene in Schwann cells and a deficit of myelination in peripheral nerves. Patients with CMT1A have reduced nerve conduction velocity, muscle wasting, hand and foot deformations and foot drop walking. Here, we evaluate the safety and efficacy of recombinant adeno-associated viral vector serotype 9 (AAV2/9) expressing GFP and shRNAs targeting Pmp22 mRNA in animal models of Charcot-Marie-Tooth disease 1 A. Intra-nerve delivery of AAV2/9 in the sciatic nerve allowed widespread transgene expression in resident myelinating Schwann cells in mice, rats and non-human primates. A bilateral treatment restore expression levels of PMP22 comparable to wild-type conditions, resulting in increased myelination and prevention of motor and sensory impairments over a twelve-months period in a rat model of CMT1A. We observed limited off-target transduction and immune response using the intra-nerve delivery route. A combination of previously characterized human skin biomarkers is able to discriminate between treated and untreated animals, indicating their potential use as part of outcome measures.

• Authors: Cristina Orden 1, Martín Santos 2, María Ceprian 3, Francisco J Tendillo 2

• Publication date: 2021 Jan

• Objective: To investigate the effect of cannabidiol (CBD) on sevoflurane minimum alveolar concentration (MACSEV) reduction produced by morphine in rats.

• Study design: Randomized, blinded trial.

• Animals: A total of 75 male Wistar Han rats weighing 276 ± 23 g (mean and standard deviation), aged 3 months.

• Methods: Cannabidiol (CBD) was prepared in an ethanol-solutol-saline vehicle. Animals were randomly divided into 15 groups and given an intraperitoneal bolus of 1, 3, 5, 6.5, 7.5 or 10 mg kg-1 of CBD alone (CBD1, CBD3, CBD5, CBD6.5, CBD7.5 and CBD10 respectively) or combined with 5 mg kg-1 of morphine (MOR+CBD1, MOR+CBD3, MOR+CBD5, MOR+CBD6.5, MOR+CBD7.5 and MOR+CBD10). While three controls groups: MOR+saline, MOR+vehicle and vehicle were given an intraperitoneal bolus of morphine with saline, morphine with vehicle or vehicle alone respectively. The MACSEV was determined from alveolar gas samples at the time of tail clamp application. The MACSEV reduction was analyzed using a one-way ANOVA followed by Tukey's test. Additionally, Kruskal-Wallis test for non-normally-distributed data was performed. Data are presented as mean ± standard deviation. P < 0.05 RESULTS: The mean MACSEV was not reduced by the action of CBD administered alone, but the addition of morphine to the different doses of CBD significantly reduced the MACSEV. That reduction was greatest in the MOR+CBD1, MOR+CBD7.5 and MOR+CBD10 groups (29 ± 5%, 32 ± 5% and 30 ± 6% respectively), less in MOR+CBD3 and MOR+CBD6.5 groups (24 ± 3% and 26 ± 4% respectively) and least in MOR+CBD5 group (17 ± 2%). However, only the MOR+CBD5 group was statistically significantly different from MOR+CBD1, MOR+CBD7.5 and MOR+CBD10 groups.

• Conclusions and clinical relevance: MACSEV in rat was unaltered by the action of CBD alone, the reduction in MACSEV produced by morphine was not enhanced by the addition of CBD at the doses studied.